Drosophila Fos mediates ERK and JNK signals via distinct phosphorylation sites.

During Drosophila development Fos acts downstream from the JNK pathway. Here we show that it can also mediate ERK signaling in wing vein formation and photoreceptor differentiation. Drosophila JNK and ERK phosphorylate D-Fos with overlapping, but distinct, patterns. Analysis of flies expressing phosphorylation site point mutants of D-Fos revealed that the transcription factor responds differentially to JNK and ERK signals. Mutations in the phosphorylation sites for JNK interfere specifically with the biological effects of JNK activation, whereas mutations in ERK phosphorylation sites affect responses to the EGF receptor-Ras-ERK pathway. These results indicate that the distinction between ERK and JNK signals can be made at the level of D-Fos, and that different pathway-specific phosphorylated forms of the protein can elicit different responses.

Sec61beta, a subunit of the protein translocation channel, is required during Drosophila development.

We have identified and isolated mutations in the first Drosophila gene encoding a subunit of the Sec61 protein translocation channel, DSec61beta. While neither the Saccharomyces cerevisiae Sec61beta nor its functional Escherichia coli homologue are essential for viability or for protein translocation, we show that DSec61beta is essential for embryonic development. Homozygous mutant embryos die at the end of embryogenesis and are impaired in the secretion of cuticle proteins from the epidermis. DSec61beta germ line clones, result in defects in dorso-ventral patterning of the egg and are consistent with affected secretion of the protein Gurken from the oocyte to the follicle cells. Clonal analyses in the imaginal discs reveal defects in adult structures, including rhabdomere morphogenesis and a reduction of the size of tarsal segments in the leg. This is the first in vivo study of a component of the protein translocation machinery in higher eukaryotes, and illustrates how a protein that has an inessential, kinetic function in single-cell organisms can become critical for the complex development of a multicellular organism.

A CREB-binding site as a target for decapentaplegic signalling during Drosophila endoderm induction.

Decapentaplegic (Dpp) is an extracellular signal of the transforming growth factor-beta family with multiple functions during Drosophila development. For example, it plays a key role in the embryo during endoderm induction. During this process, Dpp stimulates transcription of the homeotic genes Ultrabithorax in the visceral mesoderm and labial in the subjacent endoderm. Here, we show that a cAMP response element (CRE) from an Ultrabithorax enhancer mediates Dpp-responsive transcription in the embryonic midgut, and that endoderm expression from a labial enhancer depends on multiple CREs. Furthermore, the Drosophila CRE-binding protein dCREB-B binds to the Ultrabithorax CRE, and ubiquitous expression of a dominant-negative form of dCREB-B suppresses CRE-mediated reporter gene expression and reduces labial expression in the endoderm. Therefore, a CREB protein may act as a nuclear target, or as a partner of a nuclear target, for Dpp signalling in the embryonic midgut.

Defective dorsal closure and loss of epidermal decapentaplegic expression in Drosophila fos mutants.

Drosophila kayak mutant embryos exhibit defects in dorsal closure, a morphogenetic cell sheet movement during embryogenesis. Here we show that kayak encodes D-Fos, the Drosophila homologue of the mammalian proto-oncogene product, c-Fos. D-Fos is shown to act in a similar manner to Drosophila Jun: in the cells of the leading edge it is required for the expression of the TGFbeta-like Decapentaplegic (Dpp) protein, which is believed to control the cell shape changes that take place during dorsal closure. Defects observed in mutant embryos, and adults with reduced Fos expression, are reminiscent of phenotypes caused by 'loss of function' mutations in the Drosophila JNKK homologue, hemipterous. These results indicate that D-Fos is required downstream of the Drosophila JNK signal transduction pathway, consistent with a role in heterodimerization with D-Jun, to activate downstream targets such as dpp.

A comparison of primary alcoholics, secondary alcoholics, and nonalcoholic psychiatric patients on the MacAndrew Alcoholism Scale.

The MacAndrew Alcoholism (MAC) and Sc scales of the Minnesota Multiphasic Personality Inventory (MMPI) were examined in four groups of 20 male patients. Comparisons were made among primary alcoholics, secondary alcoholics (i.e., alcoholic psychiatric patients), nonalcoholic psychiatric patients (mixed diagnoses), and conservatively defined, nonalcoholic schizophrenics. Primary alcoholics scored higher on the MAC scale than did secondary alcoholics and other groups; schizophrenics scored lower than all other groups. Primary alcoholics were lower on the Sc scale than schizophrenics but did not differ from other groups. The results support MacAndrew's (1981) distinction between primary and secondary alcoholics and suggest that the MAC scale may enhance differentiation among diagnoses other than alcoholism.

Ectopic thyroid: residual function after withdrawal of treatment in infancy and later childhood.

Plasma thyroxine (T4) and thyrotrophin (TSH) were estimated in 34 children identified by neonatal hypothyroid screening and subsequently found to have ectopic thyroid tissue on isotope scan. Before treatment plasma T4 ranged from 8-143 nmol/l and TSH from 39-1,230 mU/l. After one week off treatment during their second year, repeat T4 in 26 of these cases showed a significant correlation with the pre-treatment values (r = 0.57). However, only 3 of the 5 children with pre-treatment T4 levels over 100 nmol/l at diagnosis had normal T4 values when retested. Similarly, when 10 children with pre-treatment T4 values over 65 nmol/l were retested off treatment at the ages of 5.8-8.2 years, only 4 had plasma T4 levels in the normal range. These results illustrate the wide range of thyroid function which can occur in children with ectopic thyroid tissue and indicate that some continue to have near-normal thyroid function for considerable periods. However, pre-treatment T4 results do not allow accurate identification of these latter cases.

The use of myocutaneous flaps by general surgeons.

This is a study of the use of myocutaneous flaps by general surgeons in a district general hospital over a 5 year period, and shows that such work can be satisfactorily performed by general surgeons.

Bioequivalence (bioavailability) of generic topical corticosteroids.

A new, quantitative modification of the vasoconstrictor assay was used to measure bioavailability of generic topical corticosteroid products in two categories: betamethasone valerate 0.1% cream and triamcinolone 0.1% cream. Betamethasone valerate products could be separated into two distinct categories, and triamcinolone acetonide products could be grouped into three categories of activity. A survey of local pharmacies showed that generic substitution would be made for the prescribed brand of betamethasone valerate in 58% of cases and for the prescribed triamcinolone acetonide 75% of the time. Because of the prevalence of generic substitution of products that may not have equivalent bioavailability, some standardization of the bioavailability of topical products is needed.

Use of absorbable mesh to displace bowel and avoid radiation enteropathy, during therapy of pelvic Ewing's sarcoma.

The use of absorbable polyglactin 910 mesh (Vicryl) is described in a case of Ewing's sarcoma of the pelvis. An operation was performed to hold the small bowel and colon out of the pelvis for a temporary period during which radical radiotherapy was delivered. The mesh allowed the temporary displacement of bowel and obviated bowel radiation morbidity.

Development of resistance to cephalosporins in clinical strains of Citrobacter spp.

The predominant beta-lactam antibiogram of Citrobacter freundii resembles that of Enterobacter cloacae in demonstrating resistance to cephalothin and cefoxitin with susceptibility to the newer cephalosporins. Four representative strains of C. freundii were reversibly induced to high-level beta-lactamase production by cefoxitin, and mutants with stable, high-level production were selected with cefamandole. The mutants were resistant to several second- and third-generation cephalosporins. Comparisons of isoelectric points and substrate profiles of beta-lactamases from wild-type, induced wild-type, and mutant organisms suggested a close relationship to those from E. cloacae and indicated that C. freundii mutants, like those of E. cloacae, were derepressed for production of beta-lactamase. One primary isolate of C. freundii resembled the mutants in all characteristics. In contrast, most strains of Citrobacter diversus were susceptible to all cephalosporins, and two representative strains showed neither inducible nor mutational resistance. Cefoxitin induction to enhanced beta-lactamase production was demonstrated in a cephalothin-resistant isolate, and a derepressed mutant was selected with cefotaxime. The beta-lactamase from this C. diversus strain differed substantially in substrate profile from that of E. cloacae and C. freundii.

Effect of hypermagnesemia on circulating plasma parathyroid hormone in patients on regular hemodialysis therapy.

This study was designed to assess the influence of magnesium on circulating plasma immunoreactive parathyroid hormone (iPTH) in end-stage renal disease. 20 patients receiving regular hemodialysis therapy underwent plasma measurements of iPTH and 25-hydroxycholecalciferol (25-OHCC) concentrations before and 10 weeks after the magnesium concentration in the dialysate was increased from 0.75 to 1.50 mmol/l. This resulted in a 36% rise in the mean predialysis plasma magnesium concentration from 1.25 to 1.70 mmol/l (p less than 0.001) and a 23% fall in the mean plasma iPTH concentration from 546 to 418 ng/l (p less than 0.001). Mean plasma concentrations for calcium, phosphate, and 25-OHCC also decreased, but these changes were not significant. In conclusion, we have demonstrated that a rise in plasma magnesium concentration from elevated to significantly higher levels reduces circulating plasma iPTH in normocalcemic uremic patients with initially both normal and raised plasma PTH levels.

Cystic tumours of the breast.

A retrospective survey of cystic tumours of the breast seen at the North Middlesex and St Bartholomew's Hospitals, London, has been undertaken to determine their incidence and clinical features. During the years 1967-76 4530 histological examinations were carried out on breast tissue and 1277 breast cancers diagnosed. Intracystic papillary tumours, both benign and malignant, were the least uncommon of cyst tumours, but the malignant type accounted for 0.55% of all the breast cancers. Aspects suggesting the possible presence of an intracystic tumour are discussed.

Distinct muscarinic mediation of suspected dopaminergic activity in sympathetic ganglions.

The competitive neuromuscular blocking agents, gallamine and pancuronium, enhanced the nictitating membrane contraction, in the cat, resulting from muscarine ganglionic transmission. Inhibition of ganglionic muscarinic hyperpolarization, in response to short tetanic bouts of preganglionic cervical sympathetic stimulation, was an associated event and is considered by us to be causally related. The neuroleptic drug, haloperidol, enhanced ganglionic hyperpolarization under similar stimulatory conditions, and reduced the nictitating membrane contraction elicited via ganglionic muscarine pathways, effects opposite to those produced by the skeletal muscle relaxants. Apomorphine reduced both ganglionic hyperpolarization and the ganglionic muscarinic-induced nictitating membrane contractions. The action of gallamine and pancuronium conforms to a speculative cholinergic antagonism at the specific muscarinic receptors, termed Mi, on the ganglionic dopaminergic interneuron. Haloperiodol and apomorphine are anticipated to be exerting distinct antagonistic and agonistic actions, respectively, on prejunctional dopamine receptors of the ganglionic interneuron. Ganglionic slow depolarization mediated through the muscarinic receptors, termed Me, was unaltered by any of the agents studied.

The effect of pancuronium and gallamine on muscarinic transmission in the superior cervical ganglion.

Pancuronium enhanced contraction of the nictitating membrane elicited via ganglionic muscarinic pathways in the superior cervical ganglion of the cat. In order to elucidate this phenomenon, recordings of the superior cervical ganglion surface potential were made which demonstrated that pancuronium and gallamine reduced and haloperidol enhanced ganglionic hyperpolarization without significantly altering the ganglionic slow depolarization. Pancuronium reversed the effects produced by haloperidol, whereas the latter drug was unable to antagonize those induced by pancuronium. These results allow the speculation that pharmacologically distinct muscarinic receptors reside in sympathetic ganglia, one of which is susceptible to blockade by pancuronium or gallamine.

Toxic polyneuropathy produced by methyl N-butyl ketone.

A polyneuropathy affecting a large number of workers was recently observed at a plant producing plastic-coated and color-printed fabrics. Epidemiological data suggested strongly that methyl N-butyl ketone (MBK) was responsible for the outbreak. This hypothesis is now supported by the development of a peripheral neuropathy in chickens, rats, and cats exposed to MBK at atmospheric concentrations of 200 to 600 parts per million, 24 hours per day, 7 days per week. Although the animals were exposed continuously and the affected workers were exposed intermittently, the averages of the total number of hours of exposure for development of the peripheral neutropathy in the animals and workers were remarkably close.

Kilauea volcano, hawaii: a search for the volcanomagnetic effect.

Brief excursions of magnetic field differences between a base station and two satellite station magnetometers show only slight correlation with ground tilt at Kilauea Volcano. This result suggests that only transient, localized stresses occur during prolonged periods of deformation and that the volcano can support no large-scale pattern of shear stresses.